Eribulin activates the cgas-sting pathway via the cytoplasmic accumulation of mitochondrial dna

Charles S. Fermaintt, Leila Takahashi-Ruiz, Huiyun Liang, Susan L. Mooberry, April L. Risinger

Research output: Contribution to journalArticlepeer-review

Abstract

Microtubule-targeting agents (MTAs), including both microtubule stabilizers and destabilizers are highly effective chemotherapeutic drugs used in the treatment of solid tumors and hematologic malignancies. In addition to the shared ability of all MTAs to block cell cycle progression, growing evidence shows that different agents of this class can also have mechanistically distinct effects on nonmitotic microtubule-dependent cellular processes, including cellular signaling and transport. Herein, we test the biologic hypothesis that MTAs used in the treatment of triple-negative breast cancer (TNBC) can differentially affect innate immune signaling pathways independent of their antimitotic effects. Our data demonstrate that the microtubule destabilizer eribulin, but not the microtubule stabilizer paclitaxel, induces cGAS-STING-dependent expression of interferon-b in both myeloid and TNBC cells. Activation of the cGAS-STING pathway by eribulin was further found to be mediated by the accumulation of cytoplasmic mitochondrial DNA. Together, these findings provide mechanistic insight into how eribulin can induce innate immune signaling independent of its antimitotic or cytotoxic effects.

Original languageEnglish (US)
Pages (from-to)309-318
Number of pages10
JournalMolecular pharmacology
Volume100
Issue number4
DOIs
StatePublished - Oct 1 2021

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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